In this project, we focused our studies on the genetic basis both of orthopoxvirus virulence and of host resistance to virus infection. The acquired knowledge should contribute toward development of safe, effective recombinant vaccinia virus vaccines for animal and human use. A deletion mutant of cowpox virus (CPV) has been constructed which lacks a functional gene for a 38 kDa protein which directly or indirectly inhibits the generation of chemotactic molecules which are elicited during virus replication in the CAM. Current studies have shown that the 38 dKa protein specifically blocks the generation of 14,15-diHETE molecules in two sperate cell line infected with CPV. This protein will be evaluated for its therapeutic potential. Additional studies have shown that inhibitors of the lipoxygenase pathway of arachidonic acid block the replication of orthopoxviruses as well as herpes simplex virus raising the possibility that this class of inhibitors may have broad anti-viral activity through an as yet to be determined mechanism. Eighty percent of the ectromelia virus genome has been cloned. Three host- range genes have been sequenced and are being evaluated for their importance in defining virus cell, tissue and species tropism. Studies on host resistance to disease have found that gamma interferon appears to be more important than alpha or beta interferon for recovery from infection with ectromelia virus.